Conjugates of aziridinyl-epothilone analogs and pharmaceutical compositions comprising same

Abstract

The present invention is directed to conjugated compounds comprising a folate, or an analog or derivative thereof, and an aziridinyl epothilone analog, as further described herein, and/or pharmaceutically-acceptable salts and/or solvates thereof, useful in the treatment of cancer or other folate-receptor associated conditions.

1 . A conjugated compound having the formula (I),  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically-acceptable salt and/or solvate thereof, wherein: 
 V is a folate-receptor binding moiety;  
 Q is O, S, or NR 7 ;  
 M is a releasable linker;  
 K is O, S, or NR 7a ;  
 A is —(CR 8 R 9 )—(CH 2 ) m -Z- wherein Z is —(CHR 10 )—, —C(═O)—, —C(═O)—C(═O)—, —OC(═O)—, —N(R 11 )C(═O)—, —SO 2 —, or —N(R 11 )SO 2 —;  
 B 1  is hydroxyl or cyano and R 1  is hydrogen or B 1  and R 1  are taken together to form a double bond;  
 R 2 , R 3 , and R 5  are, independently, hydrogen, alkyl, substituted alkyl, aryl or substituted aryl; or R 2  and R 3  may be taken together with the carbon to which they are attached to form an optionally substituted cycloalkyl;  
 R 4  is hydrogen, alkyl, alkenyl, substituted alkyl, substituted alkenyl, aryl, or substituted aryl;  
 R 6  is hydrogen, alkyl or substituted alkyl;  
 R 7a , R 7 , R 8 , R 9 , R 10 , and R 11  are independently hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycloalkyl, substituted heterocycloalkyl, heteroaryl, or substituted heteroaryl;  
 R 12  is H, alkyl, substituted alkyl, or halogen;  
 R 13  is aryl, substituted aryl, heteroaryl or substituted heteroaryl;  
 m is 0 to 6;  
 T has the formula:  
                     
 wherein R 14  at each occurrence is, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 q is 1 to 10; and  
 R 15 , R 16  and R 17  are independently hydrogen, lower alkyl, or substituted lower alkyl or R 16  and R 17  are taken together to form a cycloalkyl.  
 
   
   
       2 . The conjugated compound according to  claim 1 , wherein: 
 K is O;    A is C 2-4 alkylene;    B 1  is —OH;    R 2 , R 3 , R 4  and R 5  are, independently, hydrogen or lower alkyl;    R 6  is hydrogen or methyl;    R 13  is an optionally substituted 5 or 6 membered heteroaryl; and    M is —S—R 30 —O—C(═O)—, —S—R 30 —C(═O)—, or —S—R 34 R 30 —O—C(═O)— wherein    R 30  is lower alkylene or substituted lower alkylene; and R 34  is arylene or substituted arylene.    
   
   
       3 . The conjugated compound according to  claim 2  wherein R 13  is an optionally substituted thiazolyl, pyridyl, or oxazolyl.  
   
   
       4 . The conjugated compound according to  claim 2 , having the formula Ia  
     
       
         
         
             
             
         
       
     
   
   
       5 . The conjugated compound according to  claim 4  wherein V is  
     
       
         
         
             
             
         
       
     
     and 
 W and X are independently CH or nitrogen;  
 R 20  is hydrogen, amino or lower alkyl;  
 R 21  is hydrogen, lower alkyl, or forms a cycloalkyl group with R 23 ;  
 R 22  is hydrogen, lower alkyl, lower alkenyl, or lower alkynyl; and  
 R 23  is hydrogen or forms a cycloalkyl with R 21 .  
 
   
   
       6 . The conjugated compound according to  claim 5 , wherein V is  
     
       
         
         
             
             
         
       
     
   
   
       7 . A conjugated compound having the following formula Ib:  
     
       
         
         
             
             
         
       
     
     Wherein 
 V is a folate, or an analog or derivative thereof;  
 R 6  is H or lower alkyl;  
 Q is O, S, or NR 7 ;  
 M is  
                     
 R 14  at each occurrence is, independently, hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl, cycloalkylalkyl, substituted cycloalkylalkyl, heteroaryl, heteroarylalkyl, substituted heteroarylalkyl, substituted heteroaryl, heterocycloalkyl, or substituted heterocycloalkyl;  
 q is 1 to 10;  
 R 15 , R 16  and R 17  are independently hydrogen, lower alkyl or substituted lower alkyl; and  
 R 18 , R 19 , R 31 , R 32 , R 33 , R 24 , R 25 , R 26 , R 27 , R 28  and R 29  are each, independently, alkyl, substituted alkyl, cycloalkyl or substituted cycloalkyl; or any of R 18  and R 19 ; R 31  and R 32 ; R 19  and R 31 ; R 33  and R 24 ; R 25  and R 26 ; R 24  and R 25 ; or R 27  and R 28  may be taken together to form a cycloalkyl.  
 
   
   
       8 . The conjugated compound according to  claim 7  wherein each R 14  is independently H, methyl, guanidinylpropyl, —(CH 2 ) 1-2 —CO 2 H, —CH 2 —SH, —CH 2 —OH, imidazolyl(methyl), aminobutyl, or —CH(OH)—CH 3 .  
   
   
       9 . The conjugated compound according to  claim 7  wherein q is 3 and each R 14  is independently C 1  to C 3  alkyl substituted with one of —C(═O)—OH or —NH—C(═NH)—NH 2 .  
   
   
       10 . The conjugated compound according to  claim 8  wherein M is:  
     
       
         
         
             
             
         
       
     
   
   
       11 . The conjugated compound according to  claim 1  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt and/or solvate thereof.  
   
   
       12 . The conjugated compound according to  claim 11  having the formula  
     
       
         
         
             
             
         
       
     
     or a pharmaceutically acceptable salt and/or solvate thereof.  
   
   
       13 . A pharmaceutical composition comprising a conjugated compound according to  claim 1 , or a pharmaceutically-acceptable salt thereof and/or solvate thereof, in a pharmaceutically-acceptable carrier.  
   
   
       14 . A method of treating a folate-receptor associated condition in a patient in need of such treatment comprising administering to said patient a therapeutically effective amount of the conjugate compound according to  claim 1 .  
   
   
       15 . The method according to  claim 14  wherein said condition is cancer.  
   
   
       16 . The method according to  claim 15  wherein said cancer is selected from the group consisting of ovarian cancer, skin cancer, breast cancer, lung cancer, colon cancer, nose cancer, throat cancer, mammary gland cancer, liver cancer, kidney cancer, spleen cancer, brain cancer, mesothelioma, pituitary adenoma, cervical cancer, renal cell carcinoma or other renal cancer, choroid plexus carcinoma, or an epithelial tumor.  
   
   
       17 . A method of treating cancer or a proliferative disease in a patient in need of such treatment, comprising administering to said patient a therapeutically effective amount of at least one folate receptor inducer and further administering to said patient a therapeutically effective amount of at least one compound according to  claim 1 .  
   
   
       18 . The method according to  claim 17  wherein said folate receptor inducer is an estrogen receptor antagonist, a progesterone receptor agonist, an androgen receptor agonist, a glucocortioroid receptor agonist, or a retinoic acid receptor agonist.  
   
   
       19 . A method of treating a folate-receptor associated cancer in a patient in need of such treatment comprising the steps of administering a therapeutically effective amount of a conjugate compound having the following formula:  
     
       
         
         
             
             
         
       
     
     to a patient in need of such treatment, whereby the compound enters the cancer cells via a folate receptor.  
   
   
       20 . The method of  claim 19  wherein said cancer is ovarian cancer, skin cancer, breast cancer, lung cancer, colon cancer, nose cancer, throat cancer, mammary gland cancer, liver cancer, kidney cancer, spleen cancer, brain cancer, mesothelioma, pituitary adenoma, cervical cancer, renal cell carcinoma or other renal cancer, choroid plexus carcinoma, or an epithelial tumor.